Methods for treating cognitive impairments caused by traumatic brain injuries

ABSTRACT

The invention describes novel methods for treating and preventing cognitive impairments caused by traumatic brain injuries by administering a therapeutically effective amount of at least one of the cholinesterase inhibitor compounds described herein. A preferred cholinestrease inhibitor for use in the methods of the invention is donepezil hydrochloride or ARICEPT®.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.09/947,087 filed Sep. 4, 2001, now U.S. Pat. No. 6,482,838 which is acontinuation of PCT Application No. PCT/US01/07027 filed Mar. 5, 2001,which claims priority to U.S. Provisional Application No. 60/259,226filed Jan. 3, 2001, U.S. Provisional Application No. 60/220,783 filedJul. 25, 2000, U.S. Provisional Application No. 60/197,610 filed Apr.18, 2000, and U.S. Provisional Application No. 60/186,744 filed Mar. 3,2000.

FIELD OF THE INVENTION

The invention describes novel methods for treating and preventingcognitive impairments caused by traumatic brain injuries byadministering a therapeutically effective amount of at least one of thecholinesterase inhibitor compounds described herein. A preferredcholinesterase inhibitor for use in the methods of the invention isdonepezil hydrochloride or ARICEPT®.

BACKGROUND OF THE INVENTION

Novel cholinesterase inhibitors are described in U.S. Pat. No. 4,895,841and WO 98/39000, the disclosures of which are incorporated by referenceherein in their entirety. The cholinesterase inhibitors described inU.S. Pat. No. 4,895,841 include donepezil hydrochloride or ARICEPT®,which has proven to be a highly successful drug for the treatment ofAlzheimer's disease.

There is a need in the art for new and improved treatments for otherdiseases, disorders, and syndromes that are characterized by symptoms ofdementia and/or cognitive impairments. The invention is directed tothese, as well as other, important ends.

SUMMARY OF THE INVENTION

The invention describes novel methods for treating and preventingcognitive impairments caused by traumatic brain injuries (e.g., posthead trauma) by administering to a patient a therapeutically effectiveamount of at least one of the cholinesterase inhibitor compoundsdescribed herein.

The present invention is described in more detail below.

DETAILED DESCRIPTION OF THE INVENTION

“Patient” refers to animals, preferably mammals, more preferably humans.The term “patient” includes adults and children, and includes men andwomen. Children includes neonates, infants, and adolescents.

“Cognitive impairment” prefers to an acquired deficit in one or more ofmemory function, problem solving, orientation and/or abstraction thatimpinges on an individual's ability to function independently.

“Dementia” refers to a global deterioration of intellectual functioningin clear consciousness, and is characterized by one or more symptoms ofdisorientation, impaired memory, impaired judgment, and/or impairedintellect. The symptoms of “dementia” are generally worse than, and canencompass, the symptoms of “cognitive impairment.”

“Cognitive impairments caused by traumatic brain injury” refers tocognitive impairments, as defined herein, that are associated with orcaused by traumatic brain injuries, including post-head trauma and othertraumas to the head, such as, for example, traumas caused by accidentsand/or sports injuries. The traumatic brain injury may be a closed headinjury. The closed head injury may be transient or prolonged.

“Cognitive impairments caused by traumatic brain injury” includesdementia pugilistica, which is severe brain damage caused by repeatedblows to the head (e.g., from boxing). Dementia pugilistica is a chronicand progressive clinical syndrome characterized by neurological evidenceof damage to pyramidal, extrapyramidal, and cerebellar systems withassociated psychosis, dementia, personality change and impaired socialfunctioning and/or prominent signs/symptoms of Parkinsonism (e.g.,tremors, dysarthria, rigidity, bradykinesia, other extrapyramidalsigns).

In the methods described herein, the cholinesterase inhibitors of theinvention alleviate (e.g., reduce or eliminate) at least one (preferablytwo, three, or all) symptom of the disease, disorder or syndrome beingtreated. Preferably, the cholinesterase inhibitors are alleviating thesymptoms of cognitive impairments and/or dementia.

As described and defined herein, the present invention is directed tonovel methods for treating and preventing cognitive impairments causedby traumatic brain injuries by administering to a patient in needthereof a therapeutically effective amount of at least onecholinesterase inhibitor. The cholinesterase inhibitor may be any knownin the art including, for example, donepezil, tacrine, physostigmine,rivastigmine, galantamine, citicoline, velnacrine maleate, metrifonate,heptastigmine, and the like.

In one embodiment, the cholinesterase inhibitor is a compound of formulaI, a stereoisomer thereof and/or a pharmaceutically acceptable saltthereof:

wherein J is

(a) a substituted or unsubstituted group selected from the groupconsisting of (1) phenyl, (2) pyridyl, (3) pyrazyl, (4) quinolyl, (5)cyclohexyl, (6) quinoxalyl, and (7) furyl;

(b) a monovalent or divalent group, in which the phenyl may have one ormore substituents selected from (1) indanyl, (2) indanonyl, (3) indenyl,(4) indenonyl, (5) indanedionyl, (6) tetralonyl, (7) benzosuberonyl, (8)indanolyl, and (9) C₆H₅—CO—CH(CH₃)—;

(c) a monovalent group derived from a cyclic amide compound;

(d) a lower alkyl group; or

(e) a group of R²¹—CH═CH—, in which R²¹ is hydrogen or a loweralkoxycarbonyl group;

B is —(CHR²²)_(r)—, —CO—(CHR²²)_(r)—, —NR⁴—(CHR²²)_(r)—,—CO—NR⁵—(CHR²²)_(r)—, —CH═CH—(CHR²²)_(r)—, —OCOO—(CHR²²)_(r)—,—OOC—NH—(CHR²²)_(r)—, —NH—CO—(CHR²²)_(r)—, —CH₂—CO—NH—(CHR²²)_(r)—,—(CH₂)₂—NH—(CHR²²)_(r)—, —CH(OH)—(CHR²²)_(r)—, ═(CH—CH═CH)_(b)—,═CH—(CH₂)_(c)—, ═(CH—CH)_(d)═, —CO—CH═CH—CH₂—, —CO—CH₂—CH(OH)—CH₂—,—CH(CH₃)—CO—NH—CH₂—, —CH═CH═CO—NH—(CH₂)₂—, —NH—, —O—, —S—, adialkylaminoalkylcarbonyl or a lower alkoxycarbony;

wherein R⁴ is hydrogen, lower alkyl, acyl, lower alkylsulfonyl, phenyl,substituted phenyl, benzyl, or substituted benyl; R⁵ is hydrogen, loweralkyl or phenyl; r is zero or an integer of about 1 to about 10; R²² ishydrogen or methyl so that one alkylene group may have no methyl branchor one or more methyl branches; b is an integer of about 1 to about 3; cis zero or an integer of about 1 to about 9; d is zero or an integer ofabout 1 to about 5;

T is nitrogen or carbon;

Q is nitrogen, carbon or

q is an integer of about 1 to about 3;

K is hydrogen, phenyl, substituted phenyl, arylalkyl in which the phenylmay have a substituent, cinnamyl, a lower alkyl, pyridylmethyl,cycloalkylalkyl, adamantanemethyl, furylmenthyl, cycloalkyl, loweralkoxycarbonyl or an acyl; and

{overscore (------)} is a single bond or a double bond.

In the compound of formula I, J is preferably (a) or (b), morepreferably (b). In the definition of (b), a monovalent group (2), (3)and (5) and a divalent group (2) are preferred. The group (b) preferablyincludes, for example, the groups having the formulae shown below:

wherein t is an integer of about 1 to about 4; and each S isindependently hydrogen or a substituent, such as a lower alkyl having 1to 6 carbon atoms or a lower alkoxy having 1 to 6 carbon atoms. Amongthe substituents, methoxy is most preferred. The phenyl is mostpreferred to have 1 to 3 methoxy groups thereon. (S)_(t) may formmethylene dioxy groups or ethylene dioxy groups on two adjacent carbonatoms of the phenyl group. Of the above groups, indanonyl, indanedionyland indenyl, optionally having substituents on the phenyl, are the mostpreferred.

In the definition of B, —(CHR²²)_(r)—, —CO—(CHR²²)_(r)—,═(CH—CH═CH)_(b)—, ═CH—(CH₂)_(c)— and ═(CH—CH)_(d)═ are preferable. Thegroup of —(CHR²²)_(r)— in which R²² is hydrogen and r is an integer of 1to 3, and the group of ═CH—(CH₂)_(c)— are most preferable. Thepreferable groups of B can be connected with (b) of J, in particular(b)(2).

The ring containing T and Q in formula I can be 5-, 6- or 7-membered. Itis preferred that Q is nitrogen, T is carbon or nitrogen, and q is 2; orthat Q is nitrogen, T is carbon, and q is 1 or 3; or that Q is carbon, Tis nitrogen and q is 2.

It is preferable that K is a phenyl, arylalkyl, cinnamyl, phenylalkyl ora phenylalkyl having a substituent(s) on the phenyl.

In preferred embodiments, the cyclic amine compounds of formula I arethe piperidine compounds of formula II, a stereoisomer thereof and/or apharmaceutically acceptable salt thereof:

wherein R¹ is a (1) substituted or unsubstituted phenyl group; (2) asubstituted or unsubstituted pyridyl group; (3) a substituted orunsubstituted pyrazyl group; (4) a substituted or unsubstituted quinolylgroup; (5) a substituted or unsubstituted indanyl group; (6) asubstituted or unsubstituted cyclohexyl group; (7) a substituted orunsubstituted quinoxalyl group; (8) a substituted or unsubstituted furylgroup; (9) a monovalent or divalent group derived from an indanonehaving a substituted or unsubstituted phenyl ring; (10) a monovalentgroup derived from a cyclic amide compound; (11) a lower alkyl group; or(12) a group of the formula R³—CH═C—, where R³ is a hydrogen atom or alower alkoxycarbonyl group;

X is —(CH₂)_(n)—, —C(O)—(CH₂)_(n)—, —N(R⁴)—(CH₂)_(n)—,—C(O)—N(R⁵)—(CH₂)_(n)—, —CH═CH—(CH₂)_(n)—, —O—C(O)—O—(CH₂)_(n)—,—O—C(O)—NH—(CH₂)_(n)—, —CH═CH—CH═CO—, —NH—C(O)—(CH₂)_(n)—,—CH₂—C(O)—NH—(CH₂)_(n)—, —(CH₂)₂—C(O)—NH—(CH₂)_(n)—, —CH(OH)—(CH₂)_(n)—,—C(O)—CH═CH—CH₂—, —C(O)—CH₂—CH(OH)—CH₂—, —CH(CH₃)—C(O)—NH—CH₂—,—CH═CH—C(O)—NH—(CH₂)₂—, a dialkylaminoalkylcarbonyl group, a loweralkoxycarbonyl group;

where n is an integer of 0 to 6; R⁴ is a hydrogen atom, a lower alkylgroup, an acyl group, a lower alkylsulfonyl group, a substituted orunsubstituted phenyl group, or a substituted or unsubstituted benzylgroup; and R⁵ is a hydrogen atom a lower alkyl group or a phenyl group;

R² is a substituted or unsubstituted phenyl group; a substituted orunsubstituted arylalkyl group; a cinnamyl group; a lower alkyl group; apyridylmethyl group; a cycloalkylalkyl group; an adamantanemethyl group;or a furoylmethyl group; and

{overscore (------)} is a single bond or a double bond.

The term “lower alkyl group” as used herein means a straight or branchedalkyl group having 1 to 6 carbon atoms. Exemplary “lower alkyl groups”include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl,1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimthylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, and the like. The lower alkyl group ispreferably methyl, ethyl, propyl or isopropyl; more preferably methyl.

Specific examples of the substituents for the substituted orunsubstituted phenyl, pyridyl, pyrazyl, quinolyl, indanyl, cyclohexyl,quinoxalyl and furyl groups in the definition of R¹ include lower alkylgroups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, and tert-butyl groups; lower alkoxy groupscorresponding to the above-described lower alkyl groups, such as methoxyand ethoxy groups; a nitro group; halogen atoms, such as chlorine,fluorine and bromine; a carboxyl group; lower alkoxycarbonyl groupscorresponding to the above-described lower alkoxy groups, such asmethoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-propoxycarbonyl,and n-butyloxycarbonyl groups; an amino group; a lower monoalkylaminogroup; a lower dialkylamino group; a carbamoyl group; acylamino groupsderived from aliphatic saturated monocarboxylic acids having 1 to 6carbon atoms, such as acetylamino, propionylamino, butyrylamino,isobutyrylamino, valerylamino, and pivaloylamino groups;cycloalkyloxycarbonyl groups, such as a cyclohexyloxycarbonyl group;lower alkylaminocarbonyl groups, such as methylaminocarbonyl andethylaminocarbonyl groups; lower alkylcarbonyloxy groups correspondingto the above-defined lower alkyl groups, such as methylcarbonyloxy,ethylcarbonyloxy, and n-propylcarbonyloxy groups; halogenated loweralkyl groups, such as a trifluoromethyl group; a hydroxyl group; aformyl group; and lower alkoxy lower alkyl groups, such as ethoxymethyl,methoxymethyl and methoxyethyl groups. The “lower alkyl groups” and“lower alkoxyl groups” in the above description of the substituentinclude all the groups derived from the above-mentioned groups. Thesubstituent may be one to three of them, which may be the same ordifferent.

When the substituent is a phenyl group, the following group is withinthe scope of the substituted phenyl group:

wherein G is —C(O)—, —O—C(O)—, —O—, —CH₂—NH—C(O)—, —CH₂—O—, —CH₂—SO₂—,—CH(OH)—, or —CH₂—S(→O)—; E is a carbon or nitrogen atom; and D is asubstituent.

Preferred examples of the substituents (i.e., “D”) for the phenyl groupinclude lower alkyl, lower alkoxy, nitro, halogenated lower alkyl, loweralkoxycarbonyl, formyl, hydroxyl, and lower alkoxy lower alkyl groups,halogen atoms, and benzyol and benzylsulfonyl groups. The substituentmay be two or more of them, which may be the same or different.

Preferred examples of the substituent for the pyridyl group includelower alkyl and amino groups and halogen atoms.

Preferred examples of the substituent for the pyrazyl group includelower alkoxycarbonyl, carboxyl, acylamino, carbamoyl, andcycloalkyloxycarbonyl groups.

With respect to R¹, the pyridyl group is preferably a 2-pyridyl,3-pyridyl, or 4-pyridyl group; the pyrazyl group is preferably a2-pyrazinyl group; the quinolyl group is preferably a 2-quinolyl or3-quinolyl group; the quinoxalinyl group is preferably a 2-quinoxalinylor 3-quinoxalinyl group; and the furyl group is preferably a 2-furylgroup.

Specific examples of preferred monovalent or divalent groups derivedfrom an indanone having an unsubstituted or substituted phenyl ringinclude those represented by formulas (A) and (B):

where m is an integer of from 1 to 4, and each A is independently ahydrogen atom, a lower alkyl group, a lower alkoxy group, a nitro group,a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, an aminogroup, a lower monoalkylamino group, a lower dialkylamino group, acarbamoyl group, an acylamino group derived from aliphatic saturatedmonocarboxylic acids having 1 to 6 carbon atoms, a cycloalkyloxycarbonylgroup, a lower alkylaminocarbonyl group, a lower alkylcarbonyloxy group,a halogenated lower alkyl group, a hydroxyl group, a formyl group, or alower alkoxy lower alkyl group; preferably a hydrogen atom, a loweralkyl group or a lower alkoxy group; most preferably the indanone groupis unsubstituted or substituted with 1 to 3 methoxy groups.

Examples of the monovalent group derived from a cyclic amide compoundinclude quinazolone, tetrahydroisoquinolinone,tetrahydrobenzodiazepinone, and hexahydrobenzazocinone. However, themonovalent group may be any one having a cyclic amide group in thestructural formula thereof, and is not limited to the above-describedspecific examples. The cyclic amide group may be one derived from amonocyclic or condensed heterocyclic ring. The condensed heterocyclicring is preferably one formed by condensation with a phenyl ring. Inthis case, the phenyl ring may be substituted with a lower alkyl grouphaving 1 to 6 carbon atoms, preferably a methyl group, or a lower alkoxygroup having 1 to 6 carbon atoms, preferably a methoxy group.

Preferred examples of the monovalent group include the following:

In the above formulae, Y is a hydrogen atom or a lower alkyl group; Vand U are each a hydrogen atom or a lower alkoxy group (preferablydimethoxy); W¹ and W² are each a hydrogen atom, a lower alkyl group, ora lower alkoxy group; and W³ is a hydrogen atom or a lower alkyl group.The right hand ring in formulae (j) and (l) is a 7-membered ring, whilethe right hand ring in formula (k) is an 8-membered ring.

The most preferred examples of the above-defined R¹ include a monovalentgroup derived from an indanone having an unsubstituted or substitutedphenyl group and a monovalent group derived from a cyclic amidecompound.

The most preferred examples of the above-defined X include —(CH₂)_(n)—,an amide group, or groups represented by the above formulae where n is2. Thus, it is most preferred that any portion of a group represented bythe formula R¹{overscore (------)}X— have a carbonyl or amide group.

The substituents involved in the expressions “a substituted orunsubstituted phenyl group” and “a substituted or unsubstitutedarylalkyl group” in the above definition of R² are the same substituentsas those described for the above definitions of a phenyl group, apyridyl group, a pyrazyl group, a quinolyl group, an indanyl group, acyclohexyl group, a quinoxalyl group or a furyl group in the definitionof R¹.

The term “arylalkyl group” is intended to mean an unsubstituted benzylor phenethyl group or the like.

Specific examples of the pyridylmethyl group include 2-pyridylmethyl,3-pyridylmethyl, and 4-pyridylmethyl groups.

Preferred examples of R² include benzyl and phenethyl groups. The symbol{overscore (------)} means a double or single bond. The bond is a doublebond only when R¹ is the divalent group (B) derived from an indanonehaving an unsubstituted or substituted phenyl ring, while it is a singlebond in other cases.

In preferred embodiments, the compound of formula II is a compound offormula III, a stereoisomer thereof and/or a pharmaceutically acceptablesalt thereof:

wherein r is an integer of about 1 to about 10; each R²² isindependently hydrogen or methyl; K is a phenalkyl or a phenalkyl havinga substituent on the phenyl ring; each S is independently a hydrogen, alower alkyl group having 1 to 6 carbon atoms or a lower alkoxy grouphaving 1 to 6 carbon atoms; t is an integer of 1 to 4; q is an integerof about 1 to about 3; with the proviso that (S)_(t) can be amethylenedioxy group or an ethylenedioxy group joined to two adjacentcarbon atoms of the phenyl ring.

In preferred embodiments, the compound of formula III is1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine;1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-ylidenyl)methylpiperidine;1-benzyl-4-((5-methoxy-1-indanon)-2-yl)methylpiperidine;1-benzyl-4-((5,6-diethoxy-1-indanon)-2-yl)methylpiperidine;1-benzyl4-((5,6-methnylenedioxy-1-indanon)-2-yl)methylpiperidine;1-(m-nitrobenzyl)4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine;1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine;1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine;1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)propylpiperidine; 1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanon)-2-yl)methylpiperidine;1-benzyl-4-((5,6-dimethoxy-1-oxoindanon)-2-yl)propenylpiperidine;stereoisomers thereof and/or pharmaceutically acceptable salts thereof.

In more preferred embodiments, the compound of formula III is1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine, astereoisomer thereof and/or a pharmaceutically acceptable salt thereof.In the most preferred embodiment, the compound of formula m is1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidinehydrochloride or a stereoisomer thereof, which is also known asdonepezil hydrochloride or ARICEPT® (Eisai Inc., Teaneck, N.J.), andwhich has formula (IV):

The compounds of the present invention may have an asymmetric carbonatom(s), depending upon the substituents, and can have stereoisomers,which are within the scope of the invention. For example, donepezilhydrochloride can be in the forms described in Japanese PatentApplication Nos. 4-187674 and 4-21670, the disclosures of which areincorporated by reference herein in their entirety. Japanese PatentApplication No. 4-187674 describes a compound having formula (V):

which can be in the form of a pharmaceutically acceptable salt, such asa hydrochloride salt. Japanese Patent Application No. 4-21670 describescompounds having formula (VI):

which can be in the form of a pharmaceutically acceptable salt, such asa hydrochloride salt; and compounds of formula (VII):

which can be in the form of a pharmaceutically acceptable salt, such asa hydrochloride salt; and compounds of formula (VIII):

As described above, the compounds of the present invention can beadministered in the form of a pharmaceutically acceptable salt.Pharmaceutically acceptable salts are known in the art and include thoseof inorganic acids, such as hydrochloride, sulfate, hydrobromide andphosphate; and those of organic acids, such as formate, acetate,trifluoroacetate, methanesulfonate, benzenesulfonate andtoluenesulfonate. When certain substituents are selected, the compoundsof the present invention may form, for example, alkali metal salts, suchas sodium or potassium salts; alkaline earth metal salts, such ascalcium or magnesium salts; organic amine salts, such as a salt withtrimethyl-amine, triethylamine, pyridine, picoline, dicyclohexylamine orN,N′-dibenzylethylene-diamine. One skilled in the art will recognizethat the compounds of the present invention can be made in the form ofany other pharmaceutically acceptable salt.

The compounds of the present invention can be prepared by processes thatare known in the art and described, for example, in U.S. Pat. No.4,895,841, WO 98/39000, and Japanese Patent Application Nos. 4-187674and 4-21670, the disclosures of each of which are incorporated byreference herein in their entirety. Donepezil hydrochloride, a preferredcholinesterase inhibitor for use in the methods described herein, iscommercially available as ARICEPT® from Eisai Inc., Teaneck, N.J.

The dosage regimen for treating the diseases described herein with thecholinesterase inhibitors described herein is selected in accordancewith a variety of factors, including the age, weight, sex, and medicalcondition of the patient, the severity of the disease, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcholinesterase inhibitor used, whether a drug delivery system is usedand whether the cholinesterase inhibitor is administered as part of adrug combination.

In preferred embodiments, the cholinesterase inhibitors of the presentinvention are administered to treat the diseases described herein indoses of about 0.1 milligram to about 300 milligrams per day, preferablyabout 1 milligram to about 100 milligrams per day, more preferably about5 milligrams to about 10 milligrams per day. The doses can beadministered in one to four portions over the course of a day,preferably once a day. One skilled in the art will recognize that whenthe cholinesterase inhibitors of the present invention are administeredto children, the dose may be smaller than the dose administered toadults, and that the dose can be dependent upon the size and weight ofthe patient. In preferred embodiments, a child can be administered thecholinesterase inhibitors of the present invention in doses of about 0.5milligrams to about 10 milligrams per day, preferably about 1 milligramto about 3 milligrams per day.

In preferred embodiments of the methods described herein, a physiciancan administer patients donepezil hydrochloride, which is commerciallyavailable as ARICEPT® (Eisai Inc., Teaneck, N.J.), as film-coatedtablets containing 5 milligrams donepezil hydrochloride or 10 milligramsdonepezil hydrochloride. The tablets can be administered one to aboutfour times a day. In preferred embodiments, one 5 milligram or one 10milligram ARICEPT® tablet is administered once a day for the methodsdescribed herein. One skilled in the art will appreciate that whendonepezil hydrochloride is administered to children, the dose may besmaller than the dose that is administered to adults. In preferredembodiments, a child can be administered donepezil hydrochloride indoses of about 0.5 milligrams to about 10 milligrams per day, preferablyabout 1 milligram to about 3 milligrams per day.

The cholinesterase inhibitors of the present invention can beadministered orally, topically, parenterally, by inhalation (nasal ororal), or rectally in dosage unit formulations containing conventionalnontoxic pharmaceutically acceptable carriers, adjuvants, and vehiclesas desired. The term parenteral as used herein includes subcutaneous,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Preferably, the cholinesterase inhibitors of the presentinvention are orally administered as tablets. When administered tochildren, the cholinesterase inhibitors of the invention are preferablyorally administered in a liquid dosage form. It will also be preferableto orally administer the cholinesterase inhibitors in a liquid dosageform to patients, such as those being treated for schizophrenia orrelated psychiatric disorders, who are unable to take a solid dosageform. In the methods of alleviating tobacco withdrawal syndromedescribed herein, the cholinesterase inhibitors can preferably beadministered topically, most preferably in the form of a transdermalpatch.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents, suspending agents (e.g.,methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, powderedtragacanth, sodium carboxymethylcellulose, polyoxytehylene sorbitanmonolaurate and the like), pH modifiers, buffers, solubilizing agents(e.g., polyoxyethylene hydrogenated castor oil, Polysorbate 80,nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, an ethylester of castor oil fatty acid, and the like) and preservatives. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be used are water, Ringer's solution, andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally used as a solvent or suspending medium. For this purposeany bland fixed oil may be used including synthetic mono- ordiglycerides, in addition, fatty acids such as oleic acid find use inthe preparation of injectables. The preparations can be lyophilized bymethods known in the art.

Solid dosage forms for oral administration may include chewing gum,capsules, tablets, sublingual tablets, powders, granules and gels; mostpreferably tablets. In such solid dosage forms, the active compound maybe admixed with one or more inert diluents such as lactose or starch. Asis normal practice, such dosage forms may also comprise other substancesincluding lubricating agents such as magnesium stearate. In the case ofcapsules, tablets, and pills, the dosage forms may also comprisebuffering agents. The tablets can be prepared with enteric or filmcoatings, preferably film coatings.

In addition to the active ingredient, the tablets preferably compriselactose monohydrate, corn starch, microcrystalline cellulose,hydroxypropyl cellulose, and magnesium stearate; while the film-coatingon the tablet preferably comprises talc, polyethylene glycol,hydroxpropyl methylcellulose, titanium dioxide, and, optionally, othercoloring agents, such as yellow iron oxide.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, and syrups containinginert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

For administration by inhalation, the compositions of the invention canbe delivered from an insufflator, a nebulizer or a pressured pack orother convenient mode of delivering an aerosol spray. Pressurized packscan include a suitable propellant. Alternatively, for administration byinhalation, the compositions can be administered in the form of a drypowder composition or in the form of a liquid spray.

Suppositories for rectal administration can be prepared by mixing theactive compounds with suitable nonirritating excipients such as cocoabutter and polyethylene glycols that are solid at room temperature andliquid at body temperature.

For topical administration to the epidermis, the cholinesteraseinhibitors can be formulated as ointments, creams or lotions, or as theactive ingredient of a transdermal patch. The cholinesterase inhibitorscan also be administered via iontophoresis. Ointments, creams andlotions can be formulated with an aqueous or oily base with the additionof suitable thickening and/or gelling agents. Alternatively, ointments,creams and lotions can be formulated with an aqueous or oily base andcan also contain one or more emulsifying agents, stabilizing agents,dispersing agents, suspending agents, thickening agents, and/or coloringagents. As creams or lotions, the cholinesterase inhibitors can be mixedto form a smooth, homogeneous cream or lotion with, for example, one ormore of a preservative (e.g., benzyl alcohol 1% or 2% (wt/wt)),emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purifiedwater, sorbitol solution. Such topically administrable compositions cancontain polyethylene glycol 400. To form ointments, the cholinesteraseinhibitors and/or migraine drugs can be mixed with one or more of apreservative (e.g., benzyl alcohol 2% (wt/wt)), petrolatum, emulsifyingwax, and Tenox (II) (e.g., butylated hydroxyanisole, propyl gallate,citric acid, propylene glycol). Woven pads or rolls of bandagingmaterial, e.g., gauze, can be impregnated with the transdermallyadministrable compositions for topical application.

The cholinesterase inhibitors can also be topically applied using atransdermal system, such as one of an acrylic-based polymer adhesivewith a resinous crosslinking agent impregnated with the cholinesteraseinhibitors and laminated to an impermeable backing. For example, thecholinesterase inhibitors can be administered in the form of atransdermal patch, such as a sustained-release transdermal patch.Transdermal patches can include any conventional form such as, forexample, an adhesive matrix, a polymeric matrix, a reservoir patch, amatrix- or monolithic-type laminated structure, and are generallycomprised of one or more backing layers, adhesives, penetrationenhancers, and/or rate-controlling membranes. Transdermal patchesgenerally have a release liner which is removed to expose theadhesive/active ingredient(s) prior to application. Transdermal patchesare described in, for example, U.S. Pat. Nos. 5,262,165, 5,948,433,6,010,715 and 6,071,531, the disclosures of which are incorporated byreference herein in their entirety.

While the cholinesterase inhibitors of the invention can be administeredas the sole active pharmaceutical agent in the methods described herein,they can also be used in combination with one or more compounds whichare known to be therapeutically effective against the specific diseasethat one is targeting for treatment.

Each of the patents and publications cited herein are incorporated byreference herein in their entirety.

It will be apparent to one skilled in the art that various modificationscan be made to the invention without departing from the spirit or scopeof the appended claims.

What is claimed is:
 1. A method of treating one or more cognitiveimpairments caused by a closed head injury in a patient in need thereofcomprising administering a therapeutically effective amount of acompound of formula (IV) or a pharmaceutically acceptable salt thereof:

or a stereoisomer thereof.
 2. The method of claim 1, wherein the closedhead injury is transient.
 3. The method of claim 1, wherein the closedhead injury is prolonged.
 4. The method of claim 1, wherein the compoundof formula (IV) is:

or a stereoisomer thereof.
 5. The method of claim 1, wherein thecompound of formula (VI) is a compound of formula (VI) or apharmaceutically acceptable salt thereof:


6. The method of claim 1, wherein the compound of formula (IV) is acompound of formula (VII) or a pharmaceutically acceptable salt thereof:


7. The method of claim 1, wherein the compound of formula (IV), thestereoisomer thereof, or the pharmaceutically acceptable salt thereof isadministered in an amount of about 1 mg to about 100 mg.
 8. The methodof claim 1, wherein the compound of formula (IV), the stereoisomerthereof, or the pharmaceutically acceptable salt thereof is administeredin an amount of about 5 mg to about 10 mg.
 9. The method of claim 1,wherein the compound of formula (IV), the stereoisomer thereof, or thepharmaceutically acceptable salt thereof is administered in an amount ofabout 5 milligrams.
 10. The method of claim 1, wherein the compound offormula (IV), the stereoisomer thereof, or the pharmaceuticallyacceptable salt thereof is administered in an amount of about 10milligrams.
 11. The method of claim 1, wherein the compound of formula(IV), the stereoisomer thereof, or the pharmaceutically acceptable saltthereof is orally administered.
 12. The method of claim 11, wherein thecompound of formula (IV), the stereoisomer thereof, or thepharmaceutically acceptable salt thereof is orally administered in theform of a tablet.
 13. The method of claim 1, wherein the compound offormula (IV), the stereoisomer thereof, or the pharmaceuticallyacceptable salt thereof is topically administered to the epidermis. 14.The method of claim 1, wherein the patient is a human adult.
 15. Themethod of claim 1, wherein the patient is a human child.
 16. The methodof claim 1, wherein the compound of formula (IV), the stereoisomerthereof, or the pharmaceutically acceptable salt thereof is administeredby nasal inhalation.